Salvianolic acid B protects against ANIT-induced cholestatic liver injury through regulating bile acid transporters and enzymes, and NF-κB/IκB and MAPK pathways
- 85 Downloads
The purpose of this study was to investigate the pharmacological effects of salvianolic acid B (SA-B) on α-naphthylisothiocyanate (ANIT)-induced cholestatic liver injury with the focus on bile acid homeostasis and anti-inflammatory pathways. Rats were randomly assigned into four groups. The control group was given normal saline (i.p.) for 7 consecutive days and on the 5th day was given the vehicle (i.g.). Model group was treated with normal saline (i.p.) for 7 days and administrated with ANIT (75 mg/kg, i.g.) on the 5th day. The SA-B groups were treated with SA-B (15 mg/kg and 30 mg/kg, i.p.) for 7 consecutive days as well as ANIT (75 mg/kg, i.g.) on the 5th day. We found that the serum levels of ALT, γ-GT, TBA, and other liver function indexes were found to be lower in the SA-B treatment groups than in the model group. SA-B also upregulated the transporters and enzymes involved in bile acid homeostasis such as Bsep, Oatp2, and Cyp3a2 in rats and BSEP, CYP3A4, and OATP2 in human cell lines. Moreover, SA-B suppressed NF-κB translocation into the nucleus, inhibited phosphorylation of p38 and JNK, and inhibited inflammation markers including IL-1β, IL-6, TGF-β, TNF-α, and COX-2 to extenuate cholestatic liver injury both in vivo and vitro. Taken together, our findings suggest that anti-cholestatic effects of SA-B may be associated with its ability to regulate NF-κB/IκB and MAPK inflammatory signaling pathways to inhibit inflammation and regulate transporters and enzymes to maintain bile acid homeostasis.
KeywordsCholestatic liver injury SA-B Inflammation Bile acid homeostasis
Salvianolic acid B
Bile salt export pump
Multidrug resistance-associate protein 3
Cytochrome P450 3A4
Uridine diphosphate-5′-glucuronosyltransferase 1A1
Tumor necrosis factor-α
Organic anion transporting polypeptide 2
Transforming growth factor-β
Cytochrome P450 3a2
Total bile acid
S.L., R.W. and F.Y. conceived and designed the research. S.L. and B.W. conducted all experiments. Y.W. and R.W. gave comments in the experimental design and manuscript. F.S. and Y.G. carried out data interpretation and discussion. S.L., R.W., and F.Y. wrote the manuscript. All authors read and approved the manuscript.
This work was financially supported by the National Natural Science Foundation of China (81803815) and the Fund of Shanghai Science and Technology Committee (17401900800).
Compliance with ethical standards
All animal procedures in this work were conducted according to the Animal Ethics Committee, Shanghai 9th People’s Hospital, Shanghai Jiao Tong University School of Medicine, China.
Conflict of interest
The authors declare that they have no conflicts of interest.
- Baek HS, Park N, Kwon YJ, Ye DJ, Shin S, Chun YJ (2017) Annexin A5 suppresses cyclooxygenase-2 expression by downregulating the protein kinase C-ζ-nuclear factor-κB signaling pathway in prostatfe cancer cells. Oncotarget 8:74263–74275Google Scholar
- Wang Y, Wang R, Wang Y, Peng R, Wu Y, Yuan Y (2015b) Ginkgo biloba extract mitigates liver fibrosis and apoptosis by regulating p38 MAPK, NF-κB/IκBα, and Bcl-2/Bax signaling. Drug Des Dev Ther 9:6303–6317Google Scholar
- Yang T, Mei H, Xu D, Zhou W, Zhu X, Sun L, Huang X, Wang X, Shu T, Liu J, Ding J, Hassan HM, Zhang L, Jiang Z (2017) Early indications of ANIT-induced cholestatic liver injury: alteration of hepatocyte polarization and bile acid homeostasis. Food and chemical toxicology: an international journal published for the. Br Ind Biol Res Assoc 110:1–12. https://doi.org/10.1016/j.fct.2017.09.051 Google Scholar
- Zhou Y et al (2018) SB203580 attenuates acute lung injury and inflammation in rats with acute pancreatitis in pregnancy. InflammopharmacologyGoogle Scholar